Electrical stimulation of the periaqueductal gray matter in the rat mesen- cephalon for 20 min. produced a rapid suppression of splenic NK cell activity when assessed 3 hrs following the termination of stimulation. The most active sites in suppressing NK cell activity were found in the caudal PAG, just lateral to the dorsal raphe. Injections of morphine into a similar region were also found to suppress NK cell activity. Additional sites that were involved in alterations of this immunological parameter were found in the caudal periventricular gray matter extending from the level of the posterior hypothalamus to the red nucleus. The selective mu opiate receptor agonist (DAGO), the selective kappa receptor agonist (S,S-U50-488) and the selective delta receptor agonist (DPDPE) were injected into the lateral ventricle of the rat brain. Three hours later the spleens were removed and assayed for NK activity. DAGO (6-60nmol) reduced NK cell activity while the other two ligands had no effect even at the highest doses employed. This suggests that the central actions of opiates on immune function are mediated through mu opiate receptors. Systemically injected cocaine (30-40 mg/kg) was found to suppress immune function when assessed 30 min. following injection. This appears to be a peripherally mediated action since intraventricularly administered cocaine did not produce a similar effect.